Method for producing chlorobenzoxazolene

ABSTRACT

The invention relates to a process for preparing chlorobenzoxazoles of the formula (I),                    
     in which R 1 , R 2  and R 4  are as defined in claim 1 and 
     in case (a) R 3 =H, halogen, CN, NO 2 , C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy, aryl or aryloxy, where each of the 4 lastmentioned radicals is unsubstituted or substituted, or 
     in case (b) R 3 =chlorine, 
     which comprises reacting benzoxazoles of the formula (II), in which R 1 , R 2  and R 4  are as defined in formula (I) and R 3  in case (a) is as defined in formula (I) and R 3  in case (b) is hydrogen, 
     in the presence of an acidic catalyst with a chlorinating agent to give the monochlorination product (I) or in case (b) with an excess of the chlorinating agent to give the dichlorination product (I) in which R 3 =chlorine.

This application is a 371 of PCT/EP98/07969 Dec. 8, 1998.

The invention relates to the technical field of the processes forpreparing intermediates which can be employed for syntheses of activecompounds, for example active compounds for crop protection agents orpharmaceuticals.

Chlorobenzoxazoles have already attained great importance asintermediates for crop protection agents and pharmaceuticals. Theirproperties and processes for their preparation are described, interalia, in DE-A-3207153; EP-A-43573 and GB-A-913910.

Using processes from the abovementioned publications, chlorobenzoxazolescan be prepared, for example, from 2-mercapto-1,3-benzoxazoles byexchanging the mercapto group with chlorine using various chlorinatingagents. Sulfur chlorides requiring disposal are obtained as byproducts.

A further preparation method involves appropriately substituted1,3-benzoxazol-2-ones which are converted into chlorobenzoxazoles usingan excess of phosphorus pentachloride (EP-A-572893; EP-A-141053;DE-A-3406909). In the case of the preparation of2,6-dichlorobenzoxazole, for example, 6-chlorobenzoxazol-2-one isemployed. The reprocessing of the excess of PCl₅ employed in thisprocess requires a special effort.

It is already known that the unsubstituted thioanalog 1,3-benzothiazolecompound can be converted into 2-chlorobenzo-1,3-thiazole by directchlorination in the presence of chlorination catalysts (DE-A-3234530).However, this selective monochlorination reaction is not known for theanalogous benzoxazole; on the contrary, DE-A-2059725 shows that in thiscase perchlorination occurs in the molecule, without any selectivity inthe occupation of the possible substitution sites.

An alternative process for preparing chlorobenzoxazoles is requiredwhich does not have the disadvantages of the abovementioned processes.Surprisingly, it has now been found that chlorobenzoxazoles can beobtained from benzoxazoles by direct chlorination. Bothmonochlorinations and, alternatively, certain dichlorinations can becarried out in this process.

The invention accordingly provides a process for preparingchlorobenzoxazoles of the formula (I),

in which R¹, R² and R⁴ are each, independently of one another, H,halogen, CN, NO₂, C₁-C₅-alkyl, C₁-C₅-alkoxy, aryl or aryloxy, where eachof the 4 lastmentioned radicals is unsubstituted or substituted, and

(Case a) R³=H, halogen, CN, NO₂, C₁-C₅-alkyl, C₁-C₅-alkoxy, aryl oraryloxy, where each of the 4 lastmentioned radicals is unsubstituted orsubstituted, or

(Case b) R³=chlorine,

which comprises reacting benzoxazoles of the formula (II),

 in which R¹, R² and R⁴ are as defined in formula (I) and R³ in case (a)is as defined in formula (I) and R³ in case (b) is hydrogen,

in the presence of an acidic catalyst with a chlorinating agent to givethe monochlorination product (I) or in case (b) with an excess of thechlorinating agent to give the dichlorination product (I) in whichR³=chlorine.

According to the invention, the 2-chloroderivatives of the formula (I)can be prepared selectively in high yield and purity. Moreover, ourexperiments show that, if the chlorination reaction of benzoxazoles,preferably of unsubstituted benzoxazole, to the corresponding2-chlorobenzoxazole is continued using excess chlorinating agent,2,6-dichlorinated benzoxazoles, preferably 2,6-dichlorobenzoxazole, canbe obtained selectively. Such a selectivity was unforeseeable.

Owing to the results described in DE-A-2059725 the chlorination ofbenzoxazole was expected to result in unselective polychlorination.Furthermore, it was not expected that the conditions described for thechlorination of benzothiazole to give 2-chlorobenzothiazole(DE-A-3234530) could be transferred to the benzoxazole molecule, sincethe benzoxazole skeleton and in particular benzoxazole itself is knownto be a much more sensitive (reactive) molecule system and molecule,respectively. It was therefore possible to explain the technicalteachings from DE-A-2059725 and DE-A-3234530 without any contradiction.Surprisingly, however, it is possible to carry out selectivechlorinations under the conditions according to the invention even withbenzoxazoles, and the chloroderivatives of the formula (I) are usuallyobtained in high yield and selectivity.

Of particular interest are processes according to the invention forpreparing chlorobenzoxazoles of the abovementioned formula (I),

in which R¹, R² and R⁴ are each, independently of one another, H,halogen, CN, NO₂, C₁-C₅-alkyl, C₁-C₅-haloalkyl, C₁-C₅-alkoxy,C₁-C₅-haloalkoxy, phenyl or phenoxy, where each of the 2 lastmentionedradicals is unsubstituted or substituted by one or more radicalsselected from the group consisting of halogen, CN, NO₂, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,

preferably H, halogen, such as fluorine, chlorine, bromine or iodine,methyl, ethyl, methoxy, ethoxy, CF₃, CCl₃, OCF₃ or OCHF₂, in particularH or chlorine, and

(Case a) R³ in formula (I) is a radical selected from the group of theradicals possible for R¹, R² and R⁴, preferably H or chlorine, or

(Case b) R³ in formula (I) is chlorine.

In the formulae (I) and (II), the radicals alkyl, alkoxy, haloalkyl,haloalkoxy, and also the corresponding unsaturated and/or substitutedradicals, can in each case be straight-chain or branched in the carbonskeleton. Unless specifically defined, the lower carbon skeletons, forexample those having 1 to 4 carbon atoms and 2 to 4 carbon atoms in thecase of unsaturated groups, are preferred for these radicals. Alkylradicals, also in composite meanings, such as alkoxy, haloalkyl and thelike, are, for example, methyl, ethyl, n- or i-propyl, n-, i-, t- or2-butyl, pentyls, hexyls, such as n-hexyl, i-hexyl and1,3-dimethylbutyl, heptyls, such as n-heptyls, 1-methylhexyl and1,4-dimethylpentyl.

Halogen is, for example, fluorine, chlorine, bromine or iodine,haloalkyl, -alkenyl and -alkynyl are alkyl, alkenyl and alkynyl,respectively, which are partially or fully substituted by halogen,preferably by fluorine, chlorine and/or bromine, in particular byfluorine or chlorine, for example CF₃, CHF₂, CH₂F, CF₃CF₂, CH₂FCHCl₂,CCl₃, CHCl₂, CH₂CH₂Cl; haloalkoxy is, for example, OCF₃, OCHF₂, OCH₂F,CF₃CF₂O, OCH₂CF₃ and OCH₂CH₂Cl; this applies correspondingly tohaloalkenyl and other halogen-substituted radicals.

Aryl is a monocyclic, carbocyclic aromatic ring which, in thesubstituted case, also includes a bi- or polycyclic aromatic system,which contains at least one aromatic ring and optionally furtheraromatic rings or partially unsaturated or saturated rings; aryl is, forexample, phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl,pentalenyl, fluorenyl and the like, preferably phenyl. Aryloxy ispreferably an oxy radical which corresponds to the abovementioned arylradical, in particular phenoxy.

Substituted radicals, such as substituted alkyl, aryl, phenyl orphenoxy, are, for example, substituted radicals which are derived fromthe unsubstituted parent compound, the substituents being, for example,one or more, preferably 1, 2 or 3, radicals selected from the groupconsisting of halogen, alkoxy, haloalkoxy, alkylthio, hydroxyl, amino,nitro, cyano, azido, alkoxycarbonyl, alkylcarbonyl, formyl, carbamoyl,mono- and dialkylaminocarbonyl, substituted amino, such as acylamino,mono- or dialkylamino, and alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkyl sulfonyl and, in the case of cyclic radicals,also alkyl and haloalkyl. Preferred radicals having carbon atoms arethose having 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms.Preference is usually given to substituents selected from the groupconsisting of halogen, for example fluorine and chlorine, C₁-C₄-alkyl,preferably methyl or ethyl, C₁-C₄-haloalkyl, preferably trifluoromethyl,C₁-C₄-alkoxy, preferably methoxy or ethoxy, C₁-C₄-haloalkoxy, nitro andcyano. Particular preference here is given to the substituents methyl,methoxy and chlorine.

The starting materials, benzoxazoles of the formula (II), can beprepared in a known manner or analogously to known processes.Benzoxazoles are obtained, for example, by reacting 2-aminophenols withorthoformic esters or with formic acid or formamide (Houben-Weyl,“Methoden der organischen Chemie”, Vol. E8a).

Solvents which are suitable for the chlorination reaction are organic orinorganic solvents which are inert under the reaction conditions orparticipate in the reaction in a suitable manner, like those which arecustomarily used in halogenation reactions, or mixtures thereof. Inspecific cases, it is also possible to employ the reaction components assolvents.

Examples of suitable organic solvents are

aromatic or aliphatic hydrocarbons, such as benzene, toluene, xylene andparaffins,

halogenated aliphatic or aromatic hydrocarbons, for example chlorinatedalkanes and alkenes, chlorobenzene, o-dichlorobenzene,

nitrites, such as acetonitrile,

carboxylic acids and derivatives thereof, such as acetic acid or estersthereof.

Examples of suitable inorganic solvents are

phosphorus oxychloride or SOCl₂, which are additionally also suitablefor use as chlorinating agents.

In an advantageous manner, it is also possible to carry out the reactionneat, i.e. in the melt of the starting material (II) or in the melt ofthe product (I), or in mixtures thereof.

Suitable catalysts are acidic substances or mixtures thereof, forexample mineral acids or acidic salts thereof; acidic ion exchangers;zeolites (H form); other acidic minerals, such as montmorillonite, orLewis acids, for example salts of transition metals, such as FeHal₃,AlHal₃, Sb₂Hal₅, ZnHal₂, SnHal₂, SnHal₄, TiHal₄, CuHal, CuHal₂, and thelike; Hal is in each case a halogen selected from the group consistingof fluorine, chlorine, bromine and iodine, preferably chlorine, bromineor iodine, in particular chlorine. Preference is given to using iron(III) chloride, aluminum trichloride or montmorillonite, in particularFeCl₃ or AlCl₃.

The amount of catalyst can be varied within a wide range. The optimumamount of catalyst depends on the individual catalyst and is, forexample, from 0.05 to 10 mol percent, preferably from 0.1 to 3 molpercent, of catalyst, based on the amount of compound of the formula(II) employed.

Depending on the solvent, the specific compounds of the formula (I) and(II), the catalysts and the chlorinating agent, the temperatures atwhich the reactions can be carried out can be varied within a widerange; suitable reaction temperatures are usually in the range of from20 to 200° C. Depending on whether monochlorination or dichlorination isintended or whether polychlorination side reactions are possible, thereaction temperature should be chosen appropriately and, if required, beoptimized in preliminary experiments. The temperature is preferably in arange of from 60 to 150° C., in particular from 80 to 140° C.

Suitable chlorinating agents are, in general, all agents which can beused for chlorinating organic compounds, or mixtures or combinationsthereof. Suitable chlorinating agents are, for example, chlorine,SO₂Cl₂, PCl₃, PCl₅, POCl₃, SCl₂, S₂Cl₂, SOCl₂. It is also possible touse mixtures of these or with other chlorinating agents. Preference isgiven to introducing gaseous chlorine or using POCl₃, PCl₅ or SOCl₂ aschlorinating agents. Furthermore, preference is given to using acombination of PCl₃ and chlorine or PCl₅ and chlorine which generatesPCl₅ in situ. To this end, for example, PCl₃ or PCl₅ is employed insubstoichiometric amounts (in this case it is also referred to ascochlorinating agent), for example in an amount of from 0.5 to 20 molpercent, preferably 1-10 mol percent, based on the compound of theformula (II), and the remainder of chlorinating agent is introduced inthe form of chlorine gas.

The amount of chlorinating agent employed is advantageously equimolar ora slight excess, preferably of from 1.0 to 1.8 mol or else 1.0 to 1.2mol of chlorinating agent per mole of the compound of the formula (II)for monochlorination (case a), or two times the molar amount or elseslightly more than two times the molar amount, preferably from 2.0 to2.4 mol of chlorinating agent per mole of the compound of the formula(II) for dichlorination (case b). The amounts of chlorinating agent areto be reduced appropriately if the agent generates more than one molarequivalent of chlorine per mole of the agent.

The synthesis is preferably carried out by initially charging thestarting material (benzoxazole derivative of the formula (II)) in themelt or in the melt of the product or in a suitable solvent and addingthe catalyst. If appropriate, the cochlorinating agent, such as PCl₃ orPCl₅, is then added. At the desired temperature and with efficientstirring, chlorine is then introduced slowly, or another chlorinatingagent is metered in. A considerably higher rate of conversion can beachieved by carrying out the reaction in a reactor which operates by thecountercurrent principle.

The desired products are obtained selectively, in high purity and invery high yields. Very pure products can be obtained, for example, byfine distillation.

The experiments are illustrated in more detail by the examples below,without the invention being limited to these embodiments; unless statedotherwise, quantities are based on weight.

EXAMPLE 1

In a stirred flask fitted with gas inlet tube and dry-ice cooler, 20 g(0.1302 mol) of 6-chlorobenzoxazole and 50 ml of chlorobenzene were,after addition of 0.1 g of iron (III) chloride (FeCl₃), heated to 100°C. With efficient stirring, a total of 11.0 g (0.155 mol) of chlorinegas was introduced slowly under the surface of the liquid over a periodof approximately 4 hours. The progress of the reaction was monitored bygas chromatography (GC analysis). After the starting material had beenconsumed, the batch was allowed to cool. According to GC analysis, 95%of the starting material was converted into 2,6-dichlorobenzoxazole.After stripping off the solvent, the crude product could be distilledunder reduced pressure. This gave 23.07 g (0.122 mol) of2,6-dichlorobenzoxazole, purity by GC: 99.5%=93.8% of theory.

EXAMPLE 2

Using the method of Example 1, 11.9 g (0.1 mol) of 1,3-benzoxazole werereacted under the same conditions to give 2-chlorobenzoxazole. This gave14.35 g of 2-chlorobenzoxazole; GC: 99% pure=a yield of 92.5% of theory.

EXAMPLE 3

Using the method of Example 1, 11.9 g (0.1 mol) of benzoxazole werereacted, with addition of 0.5 g of montmorillonite KSF, with chlorinegas at 100° C. After addition of 1.1 times the molar amount of chlorinegas, GC showed complete conversion into 2-chlorobenzoxazole. Furtherintroduction of chlorine gas (an additional 1.0 times the molar amount)at 120-125° C. resulted in 80.6% conversion into2,6-dichlorobenzoxazole.

EXAMPLE 4

10 g (0.065 mol) of 6-chlorobenzoxazole (>99% pure) were dissolved in 70ml of phosphorus oxychloride and admixed with 0.26 g of dry aluminumtrichloride. The mixture was heated to 90° C., chlorine gas was thenintroduced, with efficient stirring, under the surface of the liquid,and the progress of the reaction was monitored by gas chromatography (GCanalysis). After approximately 6 hours, the starting material had beenconsumed. The batch was cooled and the reaction mixture was transferredinto a distillation apparatus fitted with a short Vigreux column. ExcessPOCl₃ was separated off in a forerun. A fraction of pure2,6-dichlorobenzoxazole was subsequently distilled off under reducedpressure. This gave 11.6 g of 2,6-dichlorobenzoxazole having a purity byGC of more than 99%; this corresponds to a yield of more than 94% oftheory.

EXAMPLE 5

10 g (0.065 mol) of 6-chlorobenzoxazole (>99% pure) and 100 ml ofchlorobenzene, together with 13.54 g (0.065 mol) of phosphoruspentachloride and 0.05 g of iron (III) chloride (dry), were heated withstirring to 130-133° C. After approximately 6 hours, the reaction hadended. The reaction mixture was cooled and filtered through a layer ofsilica gel 60. Elution with methylene chloride and stripping off of thelow-boilers gives a product which solidifies in the cold and which,according to GC, contains no other components; yield 12.25 g of2,6-dichlorobenzoxazole (100% of theory).

EXAMPLE 6

With efficient stirring, 10 g (0.083 mol) of 1,3-benzoxazole (>99%pure), together with 100 ml of POCl₃ and 0.2 g of iron (III) chloride(dry), were heated to 100° C. At this temperature, chlorine gas wasintroduced under the surface of the liquid. GC control of the reactionshowed that initially 2-chlorobenzoxazole was formed which, with furthersubstitution, then reacted to give 2,6-dichlorobenzoxazole. Once all ofthe starting material had been consumed, the reaction was terminated.According to GC analysis, 21.5% of 2-chlorobenzoxazole and 71% of2,6-dichlorobenzoxazol had been formed. The crude mixture was worked upby distillation. POCl₃ and 2-chlorobenzoxazole were collected in a firstfraction and could be employed directly for a further batch. The secondfraction yielded 11.0 g of 2,6-dichlorobenzoxazole (GC>99% pure) (>70%of theory). Taking into account the recycling of the2-chlorobenzoxazole, a total yield of >92% of theory was obtained.

EXAMPLE 7

10 g (0.065 mol) of 6-chlorobenzoxazole, 0.45 g of phosphorustrichloride and 0.09 g of anhydrous aluminum trichloride were initiallycharged in 30 ml of phosphorus oxychloride (POCl₃). With heating andstirring, chlorine gas was introduced at a rate of 0.6 equivalent ofchlorine per hour. After an internal temperature of 80° C. had beenreached, the stream of chlorine gas was reduced to 0.6 equivalent ofchlorine per 6 hours, and the temperature was increased to 100° C. Thereaction was monitored by gas chromatography. After all of the startingmaterial had been consumed, most of the POCl₃ was distilled off and theresidue was subjected to fractional distillation under reduced pressure.This gave a pure fraction of 11.9 g of the 2,6-dichlorobenzoxazole,which solidifies on cooling (GC>99% pure) (>97% of theory).

What is claimed is:
 1. A process for preparing chlorobenzoxazoles of theformula (I),

in which R¹, R² and R⁴ are each, independently of one another, H,halogen, CN, NO₂, C₁-C₅-alkyl, C₁-C₅-alkoxy, aryl or aryloxy, where eachof the 4 lastmentioned radicals is unsubstituted or substituted, and incase (a) R³=H, halogen, CN, NO₂, C₁-C₅-alkyl, C₁-C₅-alkoxy, aryl oraryloxy, where each of the 4 lastmentioned radicals is unsubstituted orsubstituted, or in case (b) R³=chlorine, which comprises reactingbenzoxazoles of the formula (II),

 in which R¹, R² and R⁴ are as defined in formula (I) and R³ in case (a)is as defined in formula (I) and R³ in case (b) is hydrogen, in thepresence of an acidic catalyst with a chlorinating agent to give themonochlorination product (I) or in case (b) with an excess of thechlorinating agent to give the dichlorination product (I) in whichR³=chlorine.
 2. The process as claimed in claim 1, wherein R¹, R² and R⁴in formula (I) are each, independently of one another, H, halogen, CN,NO₂, C₁-C₅-alkyl, C₁-C₅-haloalkyl, C₁-C₅-alkoxy, C₁-C₅-haloalkoxy,phenyl or phenoxy, where each of the 2 lastmentioned radicals isunsubstituted or substituted by one or more radicals selected from thegroup consisting of halogen, CN, NO₂, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, and (Case a) R³ in formula (I) is aradical selected from the group of the radicals possible for R¹, R² andR⁴ or (Case b) R³ in formula (I) is chlorine.
 3. The process as claimedin claim 1, wherein the compound (I) is 2,6-dichlorobenzoxazole.
 4. Theprocess as claimed in claim 1, wherein the reaction is carried out inthe presence of an organic or inorganic solvent or neat.
 5. The processas claimed in claim 1, wherein the chlorinating agent used is chlorine,SO₂Cl₂, PCl₃, PCl₅, POCl₃, SCl₂, S₂Cl₂, SOCl₂ or a mixture of theabovementioned agents.
 6. The process as claimed in claim 1, wherein thechlorinating agent used is chlorine in combination with PCl₃ or PCl₅. 7.The process as claimed in claim 1, wherein the catalysts are employed inan amount of from 0.05 to 10 mol percent, based on the amount ofcompound of the formula (II) used.
 8. The process as claimed in claim 1,wherein the catalyst employed is montmorillonite or a Lewis acid.
 9. Theprocess as claimed in claim 1, wherein the catalyst employed is FeCl₃ orAlCl₃.
 10. The process as claimed in claim 1, wherein the reactiontemperature is from 20 to 200° C.